CN107955058A - A kind of preparation of the intermediate for being used to prepare shellfish cholic acid difficult to understand, its preparation method and shellfish cholic acid difficult to understand - Google Patents
A kind of preparation of the intermediate for being used to prepare shellfish cholic acid difficult to understand, its preparation method and shellfish cholic acid difficult to understand Download PDFInfo
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- CN107955058A CN107955058A CN201810013708.9A CN201810013708A CN107955058A CN 107955058 A CN107955058 A CN 107955058A CN 201810013708 A CN201810013708 A CN 201810013708A CN 107955058 A CN107955058 A CN 107955058A
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- 0 C[C@](CC[C@](*)([C@@](C)(CC[C@](C1)OC2OCCCC2)[C@]1(C)C1=CC)[C@@]2(C)C1=O)([C@]2(CC1)S)C1=C(C)CCC(O*)=O Chemical compound C[C@](CC[C@](*)([C@@](C)(CC[C@](C1)OC2OCCCC2)[C@]1(C)C1=CC)[C@@]2(C)C1=O)([C@]2(CC1)S)C1=C(C)CCC(O*)=O 0.000 description 5
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- KXTFNOIUXGTJNV-TZXTYRITSA-N CC(CCC(O)OCc1ccccc1)[C@@H](CC1)[C@@](C)(CC[C@@H]2[C@@](C)(CC[C@H](C3)O)[C@@H]3C3)[C@@H]1[C@@H]2C3=O Chemical compound CC(CCC(O)OCc1ccccc1)[C@@H](CC1)[C@@](C)(CC[C@@H]2[C@@](C)(CC[C@H](C3)O)[C@@H]3C3)[C@@H]1[C@@H]2C3=O KXTFNOIUXGTJNV-TZXTYRITSA-N 0.000 description 1
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- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J17/005—Glycosides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
The present invention relates to pharmaceutical technology field, specifically, is related to the preparation of the intermediate for being used to prepare shellfish cholic acid difficult to understand, its preparation method and shellfish cholic acid difficult to understand.Route provided by the invention is using acetaldehyde as electrophilic reagent, and by aldol reaction introducing vinyl compared with the method for iodoethane, yield increases substantially；Compound（V）By the way that into cyclohexylamine salt refining, product quality can be increased substantially；Reducing carbonyl may insure that vinyl is reduced after first hydrogenating double bond, and by controlling suitable temperature, the accessory substance of de- ethyl can be greatly reduced.Route reaction condition is gentle, environmentally protective, and yield is higher than existing preparation method, economical and effective, suitable for large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically, is related to a kind of intermediate for being used to prepare shellfish cholic acid difficult to understand, its system
The preparation of Preparation Method and shellfish cholic acid difficult to understand.
Background technology
Nonalcoholic fatty liver disease (NASH) is Chronic Progressive hepatopathy caused by a kind of intrahepatic fat accumulation, can be led
Cause hepatic sclerosis, hepatic failure and hepatocellular carcinoma.The NASH patient in the U.S. about 2%~5%, some epidemiology estimation results are recognized
17% is reached as high as the NASH illness rates in the U.S..NASH is currently the second largest cause of disease of U.S.'s liver transfer operation, it is contemplated that in the year two thousand twenty
The first big cause of disease of U.S.'s liver transfer operation will be become.So far, FDA not yet ratifies any effective medicine for being used to treat NASH
Thing.40,000,000,000 U.S.s but can be reached in 2025 according to the prediction of EvaluatePharme, the market scale of global NASH medicines
First dollar.
Shellfish cholic acid (OCA, method Buddhist nun ester X receptor stimulating agent) difficult to understand is granted by the breakthrough for the treatment of NASH in January, 2015 by FDA
Medicine qualification, and first, the whole world NASH medicines for entering III phases clinic, in September, 2015 formally start the III phases and study, can
To say being all to grind of greatest concern in NASH medicines one.Shellfish cholic acid difficult to understand is ratified to use on May 27th, 2016 by FDA
In treatment primary biliary cirrhosis (PBC) such a rare disease for also resulting in liver transfer operation.
WO02072598 discloses a kind of preparation method of shellfish cholic acid difficult to understand, its synthetic route is as follows：
Although the route is shorter, ethyl process yield is relatively low on second step, and uses the HMPA raw materials of carcinogenicity,
Cumbersome and of high cost, industrialization is difficult.
J.Med.Chem.2012,55,84-93 disclose a kind of preparation method of shellfish cholic acid difficult to understand, its synthetic route is as follows：
Intermediate 8 can be smoothly made in the route, but during catalytic hydrogenation, using relatively severe condition, (20 is public
Jin, 80 DEG C) double bond fails to reduce, and further enhances reaction condition, and de- ethyl product is significantly increased, and causes yield extremely low, unfavorable
Quality and cost control in product.
In view of the bent good prospect in medicine of Sha Kubi, it is therefore desirable to develop a kind of preparation of economic, safety shellfish cholic acid difficult to understand
Method.
The content of the invention
It is an object of the invention to provide a kind of economic, safety shellfish cholic acid preparation method difficult to understand.
In the first aspect of the present invention, there is provided a kind of compound as shown in formula (VI),
In the second aspect of the present invention, there is provided one kind prepares the method for the compound as shown in formula (VI), this method bag
Include following steps：
(1) compound of formula I obtains Formula II compound through esterification；
(2) Formula II compound reacts to obtain formula III compound with trim,ethylchlorosilane；
(3) formula III compound obtains formula IV compound with acetaldehyde by aldol condensation；
(4) formula IV compound hydrolyzes to obtain Formula V compound in alkaline conditions；
(5) Formula V compound is protected to obtain Formula IV compound through oxinane；
In the third aspect of the present invention, there is provided a kind of compound as shown in formula (VIII),
In the fourth aspect of the present invention, there is provided a kind of preparation method of compound as shown in formula (VIII), including such as
Lower step：
(6) Formula IV compound obtains Formula VII compound through catalytic hydrogenation
(7) Formula VII compound obtains Formula VIII compound through sodium borohydride reduction
In the fourth aspect of the present invention, there is provided a kind of preparation method of Austria's shellfish cholic acid, includes the following steps：
(8) Formula VIII compound obtains shellfish cholic acid difficult to understand (Formula IX compound) through deprotection；
Preferably, the solvent used in the step (1) is acetonitrile, DMF or tetrahydrofuran, alkali is cesium carbonate, potassium carbonate or
Sodium carbonate, benzylating reagent are benzyl chloride or cylite.
Preferably, the step (2) uses LDA (lithium diisopropylamine), LiHMDS (hexamethyldisilazide lithium)
Or LTMP (tetramethyl piperidine lithium) is used as big hindered base, solvent used is tetrahydrofuran, ether or benzene.
Preferably, the solvent used in the step (3) is tetrahydrofuran, ether or dichloromethane, lewis acid used
For boron trifluoride ether.
Preferably, the solvent used in the step (4) is methanol/water, ethanol/water or isopropanol/water, and alkali used is hydrogen
Lithia, sodium hydroxide or potassium hydroxide.
Preferably, the solvent used in the step (5) is tetrahydrofuran, has used p-methyl benzenesulfonic acid as catalysis acid.Into
One step, the step (5) further includes into salt refining step, and the alkali into used in salt refining step is cyclohexylamine, diisopropyl
Amine or triethylamine.
Preferably, step (6) solvent is sodium hydrate aqueous solution, the concentration of the sodium hydrate aqueous solution for 10~
30%；Catalyst is palladium carbon, platinum dioxide or Raney's nickel.
Preferably, step (7) solvent is methanol, ethanol, tetrahydrofuran, methanol/water or tetrahydrofuran/water, is reduced
Agent is boron hydride and its derivative, boron hydride/metal salt system；Wherein, the boron hydride includes：Lithium borohydride, boron
Sodium hydride and potassium borohydride；The metal salt system includes：Alkaline-earth halide, lanthanide series metal halide and transition metal halogen
Compound；The hydroboric derivatives include sodium cyanoborohydride, three isopropoxy potassium borohydrides or lithium triethylborohydride.
Preferably, step (8) deprotection acid used is phosphoric acid.
The invention has the advantages that using acetaldehyde as electrophilic reagent, by aldol reaction introduce vinyl with
The method of iodoethane is compared, and yield increases substantially；Compound (V) is by that into cyclohexylamine salt refining, can increase substantially production
Quality；Reducing carbonyl may insure that vinyl is reduced after first hydrogenating double bond, can be significantly by controlling suitable temperature
Reduce the accessory substance of de- ethyl.Route reaction condition is gentle, environmentally protective, and yield is higher than existing preparation method, and economy has
Effect, suitable for large-scale industrial production.
Brief description of the drawings
Fig. 1 is the hydrogen spectrogram of Formula II compound；
Fig. 2 is the hydrogen spectrogram of formula IV compound；
Fig. 3 is the hydrogen spectrogram of Formula V compound；
Fig. 4 is the hydrogen spectrogram of Formula IV compound；
Fig. 5 is the hydrogen spectrogram of Formula VII compound；
Fig. 6 is the hydrogen spectrogram of Formula VIII compound；
Fig. 7 is the hydrogen spectrogram of Formula IX compound.
Embodiment
Illustrate technical scheme, but protection scope of the present invention not limited to this below by way of specific embodiment.
Embodiment 1：Compound of formula I obtains Formula II compound through esterification
36g compound of formula I is added in 500mL reaction bulbs, adds 360mL acetonitriles, stirs lower addition 45.05g cesium carbonates,
18.91g cylites are added, are stirred overnight at room temperature, TLC detections, raw material reacts completely.Decompression boils off acetonitrile, is added in concentrate
300mL saturated sodium bicarbonate aqueous solutions and 200mL ethyl acetate, stirring dissolved clarification layering, water layer use 50mL ethyl acetate again
Extraction, merges organic layer, 100mL washings, anhydrous sodium sulfate drying, is concentrated to dryness to obtain 47.4g pale yellow oils.
The hydrogen spectrum and mass spectrometric data of Formula II compound are as follows：
1H NMR (500MHz, DMSO) δ 7.72-7.25 (m, 15H), 5.08 (q, J=12.5Hz, 6H), 4.03 (q, J=
7.1Hz, 2H), 3.60-2.60 (m, 19H), 2.57-2.48 (m, 6H), 2.48-2.33 (m, 6H), 2.27 (dt, J=15.8,
8.0Hz, 3H), 2.12-1.97 (m, 4H), 1.97-1.61 (m, 22H), 1.61-0.89 (m, 53H), 0.85 (dd, J=18.5,
6.9Hz, 11H), 0.60 (d, J=16.9Hz, 3H)
ESI-MS(m/z):480.32[M+H]+
Embodiment 2：Formula II compound reacts to obtain formula III compound with trim,ethylchlorosilane
48.4mL diisopropylamines are added into 1000mL four-hole bottles, add 260mL tetrahydrofurans, nitrogen displacement three times, drops
132mL2.5M n-BuLis are added dropwise to -50 DEG C in temperature, and about 30min is dripped off, and control temperature is no more than -30 DEG C, and drop finishes, -30 DEG C of guarantors
When temperature 3 is small.It is cooled to -65 DEG C, trim,ethylchlorosilane 34.3mL is added dropwise, 10min is dripped off, and control temperature is no more than -50 DEG C, and drop finishes
30min is kept the temperature, the 100mL tetrahydrofuran solutions of 13.2g formulas (II) compound are added dropwise, about 20min is dripped off, and drop finishes -50 DEG C of insulations
1h.TLC is detected, and raw material reacts completely.- 40 DEG C are warmed naturally to, adds 68.6mL triethylamines, temperature rises to -20 DEG C, adds
200mL saturated sodium bicarbonates, temperature rise to 20 DEG C, add 150mL ethyl acetate, stirring layering, and water layer uses 100mL acetic acid again
Ethyl ester extracts, and merges organic layer, saturated sodium bicarbonate 200mL washings, and 200mL is washed, and 200mL saturated common salt water washings are anhydrous
Sodium sulphate is dried, and is concentrated under reduced pressure into dry, obtains yellow oil 23.6g, is directly reacted in next step.
The mass spectrometric data of formula III compound is as follows：
ESI-MS(m/z):624.4[M+H]+
Embodiment 3：Formula III compound obtains formula IV compound with acetaldehyde by aldol condensation
In 500mL four-hole bottles add 23.6g formulas (III) compound 300mL dichloromethane solutions, nitrogen displacement three times,
- 65 DEG C are cooled to, adds 8.6mL acetaldehyde, 48.5mL boron trifluoride ether is added dropwise, 10min is dripped off, and control temperature is no more than -60
DEG C, insulated and stirred 4h, warms naturally to room temperature, is stirred overnight, and TLC detections, raw material reacts completely.It is slowly added to 500mL saturations
Sodium acid carbonate, has a large amount of bubbles to emerge, and layering, water layer is extracted with 200mL dichloromethane, merges organic layer, saturated sodium-chloride
200mL is washed, and anhydrous sodium sulfate drying, activated carbon decolorizing, is concentrated under reduced pressure, and obtains 20.6g rufous grease.
The hydrogen spectrum and mass spectrometric data of formula IV compound are as follows：
1H NMR (500MHz, DMSO) δ 7.517.19 (m, 1H), 5.97 (q, J=7.0Hz, 1H), 5.08 (q, J=
12.4Hz 1H), 4.51 (d, J=4.8Hz, 1H), 2.672.46 (m, 2H), 2.422.11 (m, 1H), 2.020.83 (m, 7H),
0.57(s,3H).
ESI-MS(m/z):506.34[M+H]+
Embodiment 4：Formula IV compound obtains Formula V compound through hydrolysis
20.6g formulas (IV) compound is dissolved in 180mL methanol, the 20mL aqueous solutions of 4g sodium hydroxides are added dropwise in room temperature, about
10min is dripped off, and drop finishes, and 3h is stirred at room temperature, and 40 DEG C are concentrated under reduced pressure, addition 200mL water in concentrate, 100mL methyl tertiary butyl ether(MTBE)s,
Stirring layering, water layer are extracted once with the tertiary ether of 100mL first again, and 100mL isopropyl acetates extract once, 85% phosphoric acid tune of water layer
PH to 2-3 is saved, 100mL dichloromethane is extracted twice, and merges organic layer, 50mL washings, anhydrous sodium sulfate drying, is concentrated under reduced pressure
To 14.09g dark oil things.
The hydrogen spectrum and mass spectrometric data of Formula V compound are as follows：
1H NMR (500MHz, DMSO) δ 11.92 (s, 1H), 5.97 (q, J=7.0Hz, 2H), 4.50 (d, J=4.7Hz,
2H), 3.45 (dt, J=15.1,5.2Hz, 2H), 2.61 (t, J=12.1Hz, 1H), 2.57 (d, J=4.2Hz, 1H), 2.50
(s,4H),2.33-2.04(m,8H),2.03-1.76(m,8H),1.76-1.65(m,5H),1.65-1.52(m,5H),1.52-
0.98 (m, 27H), 0.95 (s, 6H), 0.89 (d, J=6.5Hz, 6H), 0.60 (s, 6H)
ESI-MS(m/z):416.29[M+H]+
Embodiment 5：Formula V compound is protected to obtain Formula IV compound through oxinane
14.09g formulas (V) compound is dissolved in 120mL tetrahydrofurans, it is disposable to add one water of 0.32g p-methyl benzenesulfonic acid
Compound, and 3.3g 3,4- dihydropyran, are stirred at room temperature 5h.50mL saturated sodium bicarbonates, layering are added, water layer uses 50mL second again
Acetoacetic ester extracts, and merges organic layer, and 50mL saturated salt solutions wash twice, anhydrous sodium sulfate drying, activated carbon decolorizing, filtering,
It is concentrated to dryness, obtains 15.68g rufous grease.
15.68g crude products are dissolved in 100mL acetone, 2.68g cyclohexylamine is added, is stirred overnight at room temperature, there is yellow solid analysis
Go out, filter, Acetone rinse filter cake.Solid 50mL water dissolves, and adds solid phosphoric acid potassium dihydrogen and adjusts pH6-7,50mL acetic acid second
Ester is extracted twice, and merges organic layer, 50mL washings, anhydrous sodium sulfate drying, is concentrated to dryness, obtains yellow solid 5.5g.
The hydrogen spectrum and mass spectrometric data of Formula IV compound are as follows：
1H NMR (500MHz, DMSO) δ 11.92 (s, 1H), 5.99 (qd, J=7.1,3.5Hz, 1H), 4.73-4.64 (m,
1H),3.82-3.68(m,1H),3.68-3.50(m,1H),3.50-3.27(m,2H),2.68-2.55(m,1H),2.51(tt,J
=3.5,1.8Hz, 3H), 2.32-2.04 (m, 4H), 2.01-1.77 (m, 4H), 1.77-1.63 (m, 6H), 1.63-0.97 (m,
19H),0.95(s,3H),0.92-0.78(m,3H),0.60(s,3H).
ESI-MS(m/z):500.35[M+H]+
Embodiment 6：Formula IV compound obtains Formula VII compound through catalytic hydrogenation
5.5g formulas (VI) compound is dissolved in 80mL2N NaOH solutions, puts into hydriding reactor, adds 0.55gPd/C, nitrogen
Pressure testing, hydrogen are replaced three times, 19 kilograms of pressure, 50 DEG C of reaction 50h.Release of pressure, nitrogen displacement, opens kettle discharging, filters, the drift of 20mL water
Filter wash cake.The tertiary ether 50mL extractions impurity of first, adjusts pH to 6-7,50mL*3 ethyl acetate extraction product, merges with potassium dihydrogen phosphate
5g white solids are done to obtain in organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, concentration.
The hydrogen spectrum and mass spectrometric data of Formula IV compound are as follows：
1H NMR (500MHz, DMSO) δ 11.92 (s, 1H), 4.65 (dd, J=7.6,4.6Hz, 1H), 3.79-3.67 (m,
1H), 3.66-3.27 (m, 3H), 2.77 (dd, J=12.7,5.5Hz, 1H), 2.59-2.41 (m, 4H), 2.23 (ddd, J=
15.2,9.5,5.3Hz,1H),2.17-1.98(m,2H),1.98-1.62(m,8H),1.62-0.92(m,22H),0.92-0.86
(m,4H),0.86-0.72(m,4H),0.72-0.54(m,3H).
ESI-MS(m/z):502.37[M+H]+
Embodiment 7：Formula VII compound obtains Formula VIII compound through sodium borohydride reduction
2.2g formulas (VII) compound is dissolved in 80mL2N NaOH aqueous solutions, 1.0g sodium borohydrides is added, is warming up to back
Stream, reacts 3h, TLC detections, and raw material converts completely, and pH to 6-7, the extraction production of 50mL*3 ethyl acetate are adjusted with potassium dihydrogen phosphate
Product, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, concentrates and do to obtain 2g white solids.
The hydrogen spectrum and mass spectrometric data of Formula VIII compound are as follows：
1H NMR (500MHz, DMSO) δ 11.92 (s, 1H), 4.67 (dd, J=7.8,4.9Hz, 1H), 4.03 (dd, J=
8.0,4.9Hz, 1H), 3.76 (td, J=7.9,4.2Hz, 1H), 3.51 (s, 1H), 3.39 (dd, J=10.7,5.6Hz, 1H),
3.37-3.20 (m, 3H), 2.51 (dd, J=6.1,4.5Hz, 4H), 2.23 (ddd, J=15.1,9.6,5.3Hz, 1H), 2.16-
2.04(m,1H),2.04-1.59(m,11H),1.59-1.42(m,6H),1.42-0.79(m,28H),0.61(s,3H).
ESI-MS(m/z):504.38[M+H]+
Embodiment 8：Formula VIII compound obtains Formula IX compound through deprotection
2g formulas (VIII) compound is added in 20mL phosphoric acid solutions, PH3-4 is adjusted, 30min, 50mL*3 second is stirred at room temperature
Acetoacetic ester extracts, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, concentrates and do to obtain white foaming material, 10mL bis-
Chloromethanes reflux dissolved clarification, is cooled to 0-5 DEG C, crystallization 1h, filters, a small amount of dichloromethane filter cake, forced air drying, obtains white solid
Body 1.6g.
The hydrogen spectrum and mass spectrometric data of Formula IX compound are as follows：
1H NMR (500MHz, DMSO) δ 11.91 (s, 1H), 4.27 (s, 1H), 4.01 (d, J=4.9Hz, 1H), 3.50
(s, 1H), 3.21-3.05 (m, 1H), 2.55-2.46 (m, 3H), 2.23 (ddd, J=15.1,9.6,5.3Hz, 1H), 2.10
(ddd, J=15.8,9.1,7.0Hz, 1H), 1.91 (d, J=12.0Hz, 1H), 1.86-1.61 (m, 6H), 1.55-0.80 (m,
28H),0.61(s,3H).
ESI-MS(m/z):420.32[M+H]+
It is complete by above-mentioned description, relevant staff using the above-mentioned desirable embodiment according to the present invention as enlightenment
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property scope is not limited to the content on specification, it is necessary to determines its technical scope according to right.
Claims (10)
1. a kind of compound as shown in formula (VI),
A kind of 2. method for preparing compound as claimed in claim 1, it is characterised in that this method comprises the following steps：
(1) compound of formula I obtains Formula II compound through esterification；
(2) Formula II compound reacts to obtain formula III compound with trim,ethylchlorosilane；
(3) formula III compound obtains formula IV compound with acetaldehyde by aldol condensation；
(4) formula IV compound hydrolyzes to obtain Formula V compound in alkaline conditions；
(5) Formula V compound is protected to obtain Formula IV compound through oxinane；
3. a kind of compound as shown in formula (VIII),
4. one kind prepares method as claimed in claim 3, it is characterised in that this method comprises the following steps：
(6) Formula IV compound obtains Formula VII compound through catalytic hydrogenation
(7) Formula VII compound obtains Formula VIII compound through sodium borohydride reduction
5. a kind of preparation method of Austria's shellfish cholic acid, includes the following steps：
(8) Formula VIII compound obtains shellfish cholic acid difficult to understand (Formula IX compound) through deprotection；
6. the preparation method of Austria's shellfish cholic acid as claimed in claim 5, it is characterised in that the solvent used in the step (1) is
Acetonitrile, DMF or tetrahydrofuran, alkali are cesium carbonate, potassium carbonate or sodium carbonate, and benzylating reagent is benzyl chloride or cylite.
7. the preparation method of Austria's shellfish cholic acid as claimed in claim 5, it is characterised in that the step (2) uses diisopropyl
Lithium amide, hexamethyldisilazide lithium or tetramethyl piperidine lithium are as big hindered base, and solvent used is tetrahydrofuran, ether
Or benzene.
8. the preparation method of Austria's shellfish cholic acid as claimed in claim 5, it is characterised in that the solvent used in the step (3) is
Tetrahydrofuran, ether or dichloromethane, lewis acid used are boron trifluoride ether.
9. the preparation method of Austria's shellfish cholic acid as claimed in claim 5, it is characterised in that step (6) solvent is hydroxide
Sodium water solution, catalyst are palladium carbon, platinum dioxide or Raney's nickel.
10. the preparation method of Austria's shellfish cholic acid as claimed in claim 5, it is characterised in that step (7) solvent is methanol,
Ethanol, tetrahydrofuran, methanol/water or tetrahydrofuran/water, reducing agent are boron hydride and its derivative, boron hydride/metal salt
System；Wherein, the boron hydride includes：Lithium borohydride, sodium borohydride and potassium borohydride；The metal salt system includes：Alkali
Earth metal halide, lanthanide series metal halide and transition metal halide；The hydroboric derivatives include cyano group hydroboration
Sodium, three isopropoxy potassium borohydrides or lithium triethylborohydride.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
| CN111072745A (en) * | 2019-12-26 | 2020-04-28 | 中山百灵生物技术有限公司 | Preparation method of 6-methylene-7-ketocholic acid |
| ES2779985A1 (en) * | 2019-02-20 | 2020-08-21 | Moehs Iberica Sl | 3alpha-tetrahydropyranyloxy-6alpha-ethyl-7alpha-hydroxy-5ß-cholanic acid diethylamine salt (Machine-translation by Google Translate, not legally binding) |
| CN112341516A (en) * | 2020-11-14 | 2021-02-09 | 湖南科瑞生物制药股份有限公司 | 5, 6-epoxy steroid compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315320A (en) * | 2015-11-30 | 2016-02-10 | 山东省药学科学院 | Method for preparing obeticholic acid |
| CN106589039A (en) * | 2015-10-15 | 2017-04-26 | 苏州朗科生物技术有限公司 | A method for preparing obeticholic acid and related compound |
| CN107400154A (en) * | 2016-05-18 | 2017-11-28 | 北京凯因科技股份有限公司 | One kind prepares 3 α, the method for the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid |
-
2018
- 2018-01-08 CN CN201810013708.9A patent/CN107955058A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106589039A (en) * | 2015-10-15 | 2017-04-26 | 苏州朗科生物技术有限公司 | A method for preparing obeticholic acid and related compound |
| CN105315320A (en) * | 2015-11-30 | 2016-02-10 | 山东省药学科学院 | Method for preparing obeticholic acid |
| CN107400154A (en) * | 2016-05-18 | 2017-11-28 | 北京凯因科技股份有限公司 | One kind prepares 3 α, the method for the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid |
Non-Patent Citations (1)
| Title |
|---|
| VALENTINA SEPE等: "Conicasterol E, a Small Heterodimer Partner Sparing Farnesoid X Receptor Modulator Endowed with a Pregnane X Receptor Agonistic Activity, from the Marine Sponge Theonella swinhoei", 《 J. MED. CHEM.》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
| CN108680696B (en) * | 2018-05-15 | 2020-06-30 | 南京正大天晴制药有限公司 | Detection method of obeticholic acid starting material |
| ES2779985A1 (en) * | 2019-02-20 | 2020-08-21 | Moehs Iberica Sl | 3alpha-tetrahydropyranyloxy-6alpha-ethyl-7alpha-hydroxy-5ß-cholanic acid diethylamine salt (Machine-translation by Google Translate, not legally binding) |
| WO2020169643A1 (en) | 2019-02-20 | 2020-08-27 | Moehs Iberica, S.L. | DIETHYLAMINE SALT OF 3α-TETRAHYDROPYRANYLOXY-6α-ETHYL-7α-HYDROXY-5ß-CHOLANIC ACID |
| CN111072745A (en) * | 2019-12-26 | 2020-04-28 | 中山百灵生物技术有限公司 | Preparation method of 6-methylene-7-ketocholic acid |
| CN112341516A (en) * | 2020-11-14 | 2021-02-09 | 湖南科瑞生物制药股份有限公司 | 5, 6-epoxy steroid compound and preparation method and application thereof |
| CN112341516B (en) * | 2020-11-14 | 2022-07-15 | 湖南科瑞生物制药股份有限公司 | 5, 6-epoxy steroid compound and preparation method and application thereof |
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